UC San Diego

Cancer is a leading cause of death worldwide. During metastasis, cells from a primary tumor escape, invade local tissues and spread to distant organs. Even though this process represents the highest risk for cancer related death, a lot remains unknown about the principles behind its beginning and progression. The main barrier that cancer cells face at each step of the metastatic process is a complex 3D extracellular matrix (ECM), which they need to bind to, pull on and degrade. In this dissertation I use 3D culture systems to mimic a native 3D ECM in vitro, to quantitatively study the role of the ECM structure and physical properties on the development of invasive phenotypes and gene expression programs.

In chapter 1, I identified a switch to a highly persistent and polarized cell motility in a high density environment and discovered that cells undergoing this migration formed multicellular structures. Using RNA sequencing I found an upregulated 70 gene module that together with the motility response has been describes as vasculogenic mimicry (VM). I show evidence that the identified transcriptional program predicts survival in patient data across nine distinct tumor types, suggesting it may represent a conserved metastatic response.

In chapter 2, I investigate the biophysical mechanisms of cell-ECM interactions. I find that matrices with low degradability limit cell adhesion. Cells in these matrices display hallmarks of anchorage independent growth, including oxidative stress. They show decreased expression of several mTOR target genes and downregulation of TCA cycle and pyruvate metabolism pathways. Lastly, I show that as part of the response to low adhesion state, cells upregulate key NOTCH signaling molecules.

In chapter 3, I propose the use of in vivo models to deconstruct the role of collagen density in promoting cancer cell metastasis. I present preliminary data and future directions for these in vivo models.

The data presented in this dissertation provides a multiscale view of the role of the collagen microenvironment in the development of cancer cell invasive motility and metastatic phenotypes. The discoveries presented hereby highlight the value of using 3D culture assays in combination with quantitative analysis to uncover biological phenomenon with high translational potential.